Cyclic regimen of hormone administration for contraception

ABSTRACT

THE IS DISCLOSED HEREIN A METHOD OF ADMINISTERING HORMONES FOR PROVIDING CONTRACEPTION AND REGULATION OF THE MENSTRUAL CYCLE WHEREIN CONSECUTIVE DAILY DOSAGES OF A PROGESTIN ARE GIVEN DURING THE EARLY PHASE OF THE CYCLE, CONSECUTIVE DAILY DOSES OF AN ESTROGEN-PROGESTIN COMBINATION ARE GIVEN DURING THE MIDCYCLE AND CONSECUTIVE DAILY DOSAGES OF A PROGESTIN ARE GIVEN DURING THE FINAL PHASE OF THE CYCLE.

United States Patent 3,795,734 CYCLIC REGIMEN F HORMONE ADMINISTRA- TIONFOR CONTRACEPTION Joseph Guy Rochefort, St. Laurent, Quebec, Canada, as-

siguor to American Home Products Corporation, New York, N.Y. No Drawing.Filed Apr. 20, 1970, Ser. No. 30,302

- Int. Cl. A61k 17/06 US. Cl. 424-238 2 Claims ABSTRACT OF THEDISCLOSURE There is disclosed herein a method of administering hormonesfor providing contraception and regulation of the menstrual cyclewherein consecutive daily dosages of a progestin are given during theearly [phase of the cycle, consecutive daily doses of anestrogen-progestin combination are given during the midcycle andconsecutive daily dosages of a progestin are given during the finalphase of the cycle.

BACKGROUND OF THE INVENTION Two therapeutic regimens are in general usefor the present day estrogen-progestin contraceptives:

(1) Combinedthe estrogen and progestin are administered togetherStarting on day of the menstrual cycle. Day 1 is designated as the firstday of menstrual bleeding. Medication is continued until day 25 or day26. Normally menstruation occurs three to five days thereafter.

(2) Sequentialestrogen is administered alone from day 5, either for 15or 11 days, a progestin is then added for another 5 to days,respectively, to induce withdrawal bleeding.

Notwithstanding the relative Wide acceptance of these regimens, adversereactions are continually being reported for them in both the scientificliterature and the lay press. A comprehensive report with leadingreferences on the complications associated with these regimens can befound in the Second Report on Oral Contraceptives, Advisory Committee onObstetrics and Gynecology, to the Food and Drug Administration, US.Govt. Printing Ofiice, Washington, DC, August 1, 1969.

In view of the recognized risks and side elfects of the present combinedoral contraceptives, an intense effort has been mounted to developcontraceptives with reduced side effects while maintaining maximalefficacy. The most promising approaches in this direction include theuse of progestin alone therapy by either oral administration, such asthe continuous low dosage of a progestin regimen, or parenteraladministration, such as depot injection or implantation of aprogestin-filled silicone rubber implant, Second Report on OralContraceptives, cited above, pp. 16-17.

Side elfects associated with the estrogen-progestin regimens, such asnausea, weight gain, headaches and risk of thromboembolic problems,appear to be significantly reduced, rendering these progestin aloneregimens better 3,795,734 Patented Mar. 5, 1974 irregular bleeding willmake these progestin alone regimens unacceptable to most women, J. dA.Jefiery and A. I. Klopper, J. Reprod. Fert., Suppl, 4, 81 (1968) andBrit. Med. J., 4, 286 (1969).

-It is the object of this invention to disclose a new contraceptiveregimen, which is effective, well-tolerated and substantially free fromthe side effects associated with either the currently availableestrogen-progestin regimens or the newer progestin alone approaches.

SUMMARY OF THE INVENTION- The present invention relates to a newtherapeutic regimen which provides contraception and regulation of themenstrual cycle.

More particularly, the regimen of this invention involves theadministering of consecutive daily dosages of a progestin during theearly phase of the cycle followed by consecutive daily dosages of anestrogen-progestin combination during the midcycle, followed byconsecutive daily dosages of a progestin during the final phase of thecycle.

DETAILS OF THE INVENTION The intense effort to develop new techniques ofcontraception are attempts to escape from the multiple administrationsof estrogen and combined estrogen-progestin and the side effectsthereof, such as nausea, headache, weight .gain and increased risk ofthromboembolic problems.

As noted above, even the most promising of the newer techniques, thoseinvolving progestin alone approaches have serious disadvantages ofanother kind, such as irregular bleeding and cycling.

Our present knowledge does not allow us to explain the reasons for thesedisadvantages. Clinical observations to date, however, point to the factthat the progestin alone regimens impede endometrial growth, J.Martinez- Manautou et al., Fertil. Steril., 17, 49 (1966) and referencestherein. A direct consequence of this impediment of growth, I believe,is the high incidences of breakthrough bleeding and irregular cycling.

I have now developed a reliable oral contraceptive regimen, comprisingthe administration of la progestin alone with a minimal supplementalestrogen reinforcement at a critical period of the menstrual cycle. Theregimen is tolerated as well as the progestin alone regimens andovercomes the high incidences of breakthrough bleeding and irregularcycling. Indeed, an important aspect of this regimen is that it allows anormal or near normal endometrial morphology by supplying sufiicientestrogen at a critical period of the cycle, namely at the early part ofthe midcycle. By using this regimen with supplemental estrogen at thiscritical period, sufficient estrogen is available for development of aproliferative endometrium and subsequent support of the endometrium asit crosses from a proliferative phase to a secretory phase. Furthermore,since the present regimen allows an endometrial morphology similar tothe natural, menstruation follows regularly after withdrawal of themedication in the final phase of the cycle.

Another important aspect of this invention is that only a minimal amountof estrogen is employed. Consequently, the side effects associated withthe administration of large dosages of estrogens to women of childbearing age are avoided.

A preferred embodiment of the present invention is illustrated by thefollowing regimen:

For the purpose of describing this embodiment a menstrual cycle of 28days is assumed. The cycle is considered to be divided into four phases.Day 1 is the first day of menstrual bleeding of the first medicatedcycle. In the first phase, days 1, 2, 3, and 4 are medication free. On

day 5, phase II begins. For' days 5 to inclusive, a pro- 11 toinclusive, medication is combined estrogen-progestin. On day 16, phase IV'begins. For days 16 to 26 in elusive, medication reverts to progestinalone. Phase I then begins anew with no medication for days 27, 28, 1,2, 3 and 4 inclusive. (Alternatively, placebo treatment could be givenduring the phase I periods, to effect continuous pill-taking and by-passpossible patient failures.)

The actual duration of the various phases is not critical in that bothdays limiting their duration may be varied a day earlier or later. Inother words, phase III may range from days 12 to 14 inclusive (threedays) to days 10 to 16 inclusive (seven days).

The choice of suitable estrogens or progestins for use in this regimenalso is not critical provided that they have proven therapeutic utility.Examples of suitable estrogens include 170a [3 furyl]estra-1,3,5(10),7-tetraene-3,17- diol S-acetate, ethynyl estradiol,mestranol and equilin sulfate. Examples of suitable progestins includemedrogestone, ethisterone, norethindrone and clogestanone acetate.Examples of these and other suitable estrogens and progestins aredescribed in the literature; for example, U. Banik 'et al., J. Reprod.FertiL, 18, 509 (1969), C. Dodds, Clin. Pharmacol. Therap., 10, 147(1969) and E. Diczfalusy, Am. J. Obstet. Gynecol., 100, 136 (1968).

'Each of the aforenamed estrogen or progestin possesses its ownparticular degree of efiectiveness and has certain advantages over theothers so that a particular estrogen or progestin to be used in aparticular regimen of this invention will depend on the specific needsof the patient. Examples of daily dosages that may be used for thisregimen are, for the estrogens, 0.01-0.1 mg./day/patient for 170: [3furyl] estra-1,3,5(l0),7-tetraene-3,17diol and 0.1 to 0.5 mg./day3-acetate, ethynyl estradiol, or mestranol; patient for equilin sulfate;and for the progestins mentioned above 0.5 to 3.0 mg./day/patient.

The above estrogens and progestins may be administered orally in soliddosage forms such as, for example, tablets, capsules, or the like. Forthose days when the regimen calls for administration of both estrogenand progestin tablets, capsules or the like may be formulated containingboth those hormones. In tablet form the hormones are compounded withinert pharmaceutical carriers;

It is apparent that many variations may be'made in the" construction ofthe present embodiment of this invention without departing from thespirit of this invention. Such variations are intended to be includedwithin the scope of this invention.

" I claim? 1. In a method of providing contraception and regulation ofthe menstrual cycle wherein estrogen and progestin hormones areadministered to women during their menstrual cycle, the improvementwhich comprises: (a) administering orally, consecutive daily doses of aprogestin in an oral daily dosage amount of 0.05

to 3.0 milligrams per day from the fifth day to the 26th day of saidmenstrual cycle after the first day of menstrual bleeding; and

(b) administering orally, consecutive daily doses of estrogen in an oraldaily dosage amount of 0.01 to 0.10 milligram per day fona duration ofthree to seven. days within the tenth to-the 16th day of said menstrualcycle,

said specified dosages of estrogen and progestin being the onlyestrogens and progestins administered during said menstrual cycle.

2. In a method of providing contraception and regulation of themenstrual cycle wherein estrogen and progestin hormones are administeredto women during their menstrual cycle, the improvement which comprises:

(a) administering orally, consecutive daily doses of progestin selectedfrom the class consisting of medrogestone, e'thisterone, norethindroneand clogestanone acetate in an oral daily dosage amount of 0.5 to 3.0milligrams per day from the fifth day to the 26th day of said menstrualcycle after the first day of menstrual bleeding; and

(b) administering orally, consecutive daily doses of estrogen selectedfrom the class consisting of 17a- [3 furyl] estra 1,3,5(10),7-tetraene-3,17-diol 3- acetate, ethynyl estradiol, mestranol andequilin sulfate in an oral daily dosage amount of 0.01 to 0.10 milligramper day for a duration of three to seven days within the tenth to the16th day of said menstrual cycle,

said specified dosages of estrogen and progestin being the ReferencesCited Physicians Desk Reference,- 22nd ed., published by MedicalEconomics, Inc, Oradell, N.J., 1967, pp. 1064- 1067.

RICHARD L.,HUFF, Primary Examiner US. Cl. X.R. 4424l, 242, 243

333 v UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent-a'mmvsu Dated March 5, 1 7? In nwfl Di. Rochefort It is certified thaterror appears in the above-identified patent and that said Letters'Patent are hereby corrected as shown below:

The sentence starting at Column 3, line 32, should. readcorrectly asfollows:

"Examples of dailyvdosages that may be used for this regimen are, forthe estrogens, O-.Ol-O.l mg./da,y/patient for 17oL-[3-furyl1-estra.-l,3,5,(10),7-tetraene-3,l7-dio1 3'- acetate, ethynyl estradiol,or mestranol; and. 0.1-0.5 mg./day/patient for equilin sulfate; and. forthe progestins mentioned above, 0. 5 to 3.0 mg.,/d.ay pa.tient.

Signed and sealed this 17th day of September 1974.

(SEAL) Attest: V

McCOY M. GIBSON JR. o c. MARSHALL DANN o Attesting Officer 7Commissioner of Patents

